The present invention relates to chemical compounds, to their production as well as to pharmaceutical compositions containing them as well as to their use in therapy, in particular of inflammatory disease.
MCP-1 is a member of the chemokine family of pro-inflammatory cytokines which mediate leukocyte chemotaxis and activation. MCP-1 is a Cxe2x80x94C chemokine which is one of the most potent and selective T-cell and monocyte chemoattractant and activating agents known. MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases including rheumatoid arthritis, glomerular nephritides, lung fibrosis, restenosis (International Patent Application WO 94/09128), alveolitis (Jones et al., 1992, J. Immunol., 149, 2147) and asthma. Other disease areas where MCP-1 is thought to play a part in their pathology are atherosclerosis (e.g. Koch et al., 1992, J. Clin. Invest., 90, 772-779), psoriasis (Deleuran et al., 1996, J. Dermatological Science, 13, 228-236), delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease (Grimm et al., 1996, J. Leukocyte Biol., 59, 804-812), multiple sclerosis and brain trauma (Berman et al. 1996, J. Immunol., 156, 3017-3023). An MCP-1 inhibitor may also be useful to treat stroke, reperfusion injury, ischemia, myocardial infarction and transplant rejection.
MCP-1 acts through the MCP-1 receptor (also known as the CCR2 receptor). MCP-2 and MCP-3 may also act, at least in part, through the MCP-1 receptor. Therefore in this specification, when reference is made to xe2x80x9cinhibition or antagonism of MCP-1xe2x80x9d or xe2x80x9cMCP-1 mediated effectsxe2x80x9dthis includes inhibition or antagonism of MCP-2 and/or MCP-3 mediated effects when MCP-2 and/or MCP-3 are acting through the MCP-1 receptor.
Copending International Patent Application Nos. PCT/GB98/02340 and PCT/GB98/02341 describe and claim groups of compounds based upon the indole ring structure which are inhibitors of MCP-1 and therefore have applications in therapy.
The use of certain indole derivatives as NMDA antagonists is described is U.S. Pat. No. 5,051,442, WO9312780, EP-483881. Other indoles and their use as inhibitors of leukotriene biosynthesis is described in for example, EP-A-275-667.
The applicants have found a particular substitution on the indole ring produces advantageous results when used therapeutically as inhibitors of MCP-1.
According to the present invention there is provided a compound of formula (I) 
X is CH2 or SO2 
R1 is an optionally substituted aryl or heteroaryl ring;
R2 is carboxy, cyano, xe2x80x94C(O)CH2OH, xe2x80x94CONHR8, xe2x80x94SO2NHR9, tetrazol-5-yl, SO3H, or a group of formula (VI) 
where R8 is selected from hydrogen, alkyl, aryl, cyano, hydroxy, xe2x80x94SO2R12 where R12 is alkyl, aryl, heteroaryl, or haloalkyl, or R8 is a group-(CHR13)rxe2x80x94COOH where r is an integer of 1-3 and each R13 group is independently selected from hydrogen or alkyl; R9 is hydrogen, alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally subtituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a group COR14 where R14 is alkyl, aryl, heteroaryl or haloalkyl; R10 and R11 are independently selected from hydrogen or alkyl, particularly C1-4 alkyl;
R3 is hydrogen, a functional group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted cycloalkyl;
R4 is a group C(O)NR15R16 or a group (CH2)t R17;
where R15 and R16 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl provided that R15 and R16 are not both hydrogen, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms;
R17 is selected from NR18R19, OR20 or S(O)sR21 
where R18 and R19 are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms;
R20 is substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl,
R21 is optionally substituted hydrocarbyl or optionally substituted heterocyclyl, s is 0, 1 or 2 and t is an integer of from 1-4;
R5, R6 and R7 are independently selected from hydrogen, a functional group or an optionally substituted hydrocarbyl groups or optionally substituted heterocyclyl groups.
In addition, the invention provides a pharmaceutically acceptable salt, in vivo hydrolysable ester, or amide of the compound of formula (I).
Compounds of formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, they appear to inhibit RANTES induced chemotaxis. RANTES is another chemokine from the same family as MCP-1, with a similar biological profile, but acting though the CCR1 receptor. As a result, these compounds can be used to treat disease mediated by these agents, in particular inflammatory disease. Thus the invention further provides a compound of formula (I) for use in the treatment of inflammatory disease.
In this specification the term xe2x80x98alkylxe2x80x99 when used either alone or as a suffix includes straight chained, branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms. Similarly the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms. Terms such as xe2x80x9calkoxyxe2x80x9d comprise alkyl groups as is understood in the art.
The term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo. References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl. The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d includes aromatic or non-aromatic rings, for example containing from 4 to 20, suitably from 5 to 8 ring atoms, at least one of which is a heteroatom such as oxygen, sulphur or nitrogen. Nitrogen heteroatoms may be substituted for example with hydrogen or hydrocarbyl depending on the available bonds. Sulphur atoms may be in the form of S, S(O) or S(O)2.
Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
xe2x80x9cHeteroarylxe2x80x9d refers to those groups described above which have an aromatic character. The term xe2x80x9caralkylxe2x80x9d refers to aryl substituted alkyl groups such as benzyl.
Other expressions used in the specification include xe2x80x9chydrocarbylxe2x80x9d which refers to any structure comprising carbon and hydrogen atoms. For example, these may be alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.
The term xe2x80x9cfunctional groupxe2x80x9d refers to reactive substituents. They may comprise electron-donating or electron-withdrawing. Examples of such groups include halo, cyano, nitro, C(O)nR22, OR22, S(O)mR22, NR23R24, C(O)NR23R24, OC(O)NR23R24, xe2x80x94NR23C(O)nR22, xe2x80x94NR22CONR23R24, xe2x80x94Nxe2x95x90CR22R23, S(O)mNR23R24 or xe2x80x94NR23S(O)mR22 where R22, R23 and R24 are independently selected from hydrogen or optionally substituted hydrocarbyl, or R23 and R24 together form an optionally substituted heterocyclic ring as defined above, which optionally contains further heteroatoms such as sulphur, S(O), SO2, oxygen and nitrogen, n is an integer of 1 or 2, m is an integer of 1-2.
Suitable optional substituents for hydrocarbyl or groups R22, R23 and R24 include halo, perhaloalkyl such as trifluoromethyl, mercapto, hydroxy, carboxy, alkoxy, heteroaryl, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may be substituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- or di-alkyl amino, oximino or S(O)mxe2x80x2R25 where mxe2x80x2 is 1 or 2 and R25 is alkyl.
Where R23 and R24 form a heterocyclic group, this may be optionally substituted by hydrocarbyl such as alkyl as well as those substituents listed above for hydrocarbyl groups.
Suitable substituents for hydrocarbyl or heterocylic groups R5, R6 and R7 include those listed above for R22, R23 and R24.
Suitably R1 is an optionally substituted phenyl, pyridyl, naphthyl, furyl or thienyl ring, and in particular is a substituted phenyl or pyridyl ring.
Suitable optional substitutents for R1 in formula (I) include alkyl, alkenyl, alkynyl, halo, haloalkyl including perhaloalkyl such as trifluoromethyl, mercapto, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, hydroxyalkoxy, alkoxyalkoxy, alkanoyl, alkanoyloxy, cyano, nitro, amino, mono- or di-alkyl amino, oximino, sulphonamido, carbamoyl, mono or dialkylcarbamoyl or S(O)mR26 where m is as defined above and R26 is hydrocarbyl.
Particular examples of substituents R5, R6 and R7 include hydrogen, hydroxy, halo, optionally substituted alkyl such as aralkyl, carboxyalkyl or the amide derivative thereof; alkoxy; aryloxy; aralkyloxy; or an amino group which is optionally substituted with alkyl, aryl or aralkyl. A specific functional group which is suitable for R5, R6 and/or R7 is a group of sub-formula (IV). 
Particular examples of groups R5, R6 and R7 are hydrogen, hydroxy, halo or alkoxy. In particular R6 and R7 are hydrogen. R5 may be hydrogen but in addition is suitably a small subsitutent such as hydroxy, halo or methoxy.
Particular substituents for R1 include trifluoromethyl, C1-4alkyl, halo, trifluoromethoxy, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, nitro, carbamoyl, C1-4alkoxycarbonyl, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, sulphonamido, carbamoylC1-4alkyl, Nxe2x80x94(C1-4alkyl)carbamoylC1-4alkyl, Nxe2x80x94(C1-4alkyl)2carbamoyl-C1-4alkyl, hydroxyC1-4alkyl or C1-4alkoxyC1-4alkyl.
Additionally or alternatively, two such substituents together may form a divalent radical of the formula xe2x80x94O(CH2)1-4Oxe2x80x94 attached to adjacent carbon atoms on the R1 ring.
Preferred substituents for R1 are one or more non-polar substituents such as halo.
In particular, R1 is substituted by one or more halo groups, in particular chlorine. A particular example of an R1 group is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl.
Examples of groups R2 include carboxy; cyano; tetrazol-5-yl; SO3H; xe2x80x94CONHR8 where R8 is selected from cyano, hydroxy, xe2x80x94SO2R12 where R12 is alkyl such as C1-4 alkyl, aryl such as phenyl, heteroaryl or trifluoromethyl, or R8 is a group-(CHR10)rxe2x80x94COOH where r is an integer of 1-3 and each R10 group is independently selected from hydrogen or alkyl such as C1-4 alkyl; or R2 is a group xe2x80x94SO2NHR9 where R9 is an optionally substituted phenyl or an optionally substituted 5 or 6 membered heteroaryl group, or a group COR14 where R14 is alkyl such as C1-4 alkyl, aryl such as phenyl, heteroaryl or trifluoromethyl, or R2 is a group of formula (VI) 
where R10 and R11 are independently selected from hydrogen or alkyl, particularly C1-4 alkyl.
Preferably R2 is carboxy or a pharmaceutically acceptable salt or ester thereof.
Suitable groups R3 include hydrogen, fluoro, chloro, bromo, iodo, methyl, cyano, trifluoromethyl, hydroxymethyl, alkoxyalkyl such as C1-4alkoxymethyl, methoxy, benzyloxy, carboxyalkoxy such as carboxymethoxy, methylsulphanyl, methylsulphinyl, methylsulphonyl or carboxyC3-6cycloalkyl, xe2x80x94(CHR27)rxe2x80x94NR28R29 (where r is 0-2, each R27 is independently hydrogen or alkyl, in particular C1-4 alkyl, R28 and R29 are independently selected from H and C1-4alkyl or R28 and R29 together with the nitrogen to which they are attached form a 5 or 6 membered ring optionally containing one further heteroatom selected from O, N, S, S(O) or SO2. Suitably R28 and R29 together form a heterocylic ring such as morpholino or piperazinyl.
Other such groups R3 include optionally substituted aryl groups, such as optionally substituted phenyl or naphthyl group. Suitable substituents for phenyl groups R3 include one or more groups selected from chlorine, fluorine, methyl, trifluoromethyl, trifluoromethoxy, amino, formyl, phenyl, methoxy, phenoxy or phenyl.
R3 may comprise a range of substituents as listed above, in particular, hydrogen or a small substituent group such as C1-4alkyl in particular methyl, or trifluoromethyl, and is preferably hydrogen.
Suitable substitutents for hydrocarbyl and heterocyclic groups R15, R16, R18, R19, R20 and R21 as they appear in the definition of R4 include those listed above in relation to R22, R23 and R24.
Examples of R4 are groups C(O)NR15R16 where one of R15 or R16 is hydrogen or alkyl such as methyl, and the other is optionally substituted heterocyclyl or optionally substituted alkyl such as C1-2 alkyl in particular methyl, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms. Suitable optional substitutents for heterocyclic groups R15 or R16 in this case are alkyl groups such as methyl, or oxo groups. Suitable optional substitutents for alkyl groups R15 and R16 include one or more groups selected from amino; mono- or di-alkyl amino; carboxy; heterocyclyl optionally substituted with for example an alkyl groups such as methyl or an oxo group; or a group NHSO2R30 where R30 is alkyl such as methyl.
A preferred group for R4 is a group C(O)NR15R16 where one of R15 or R16 is hydrogen and the other is heterocyclyl or alkyl substituted with one or more groups selected from amino, mono- or di-alkyl amino, carboxy or optionally substituted heterocyclyl, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms.
Where one of R15 or R16 is hydrogen, examples of suitable heterocyclyls for the other include imidazole, imidazolinone, or tetrahydrothiophene-1,1-dioxide.
Preferably one of R15 or R16 is hydrogen and the other is optionally substituted alkyl, for example C1-2 alkyl. Suitable substituents include one or more groups selected from amino, mono- or di-alkyl amino, a group NHSO2R30 where R30 is methyl, carboxy or optionally substituted heterocyclyl, such as isoxazole optionally substituted mono or di-substituted with alkyl, such as methyl.
Where R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms, that ring is, for example a morpholine ring. Alternatively, R4 is a group of sub-formula (IV) as listed above.
Alternatively, R4 is preferably a group (CH2)t R17 where t is 1 and R17 is a group NR18R19. Particular examples of R18 and R19 include hydrogen and optionally substituted alkyl, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms, such as pyrazole or tetrahydropyranyl. In particular, R18 and R19 together form a morpholine ring.
X is CH2 or SO2 and is preferably CH2.
Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt.
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically acceptable esters for carboxy include alkyl esters, such as C1-6 alkyl esters for example, ethyl esters, C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxy-carbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
Suitable pharmaceutically acceptable esters of compounds of formula (I) are in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
Esters which are not in vivo hydrolysable are useful as intermediates in the production of the compounds of formula (I) and therefore these form a further aspect of the invention.
Thus examples of compounds of formula (I) include the following:
Yet a further aspect of the invention provides pharmaceutical compositions comprising a compound of formula (I) as defined above.
Compounds of formula (I) are suitably prepared by methods such as those described in International Patent Application Nos. PCT/GB98/02340 and PCT/GB98/02341.
In particular compounds of formula (I) can be prepared by reacting a compound of formula (VII) 
where X, R1, R3, R5, R6 and R7 are as defined in relation to formula (I) and R2xe2x80x2 is a group R2 as defined in relation to formula (I) or a protected form thereof, R40 is a group C(O) or a group (CH2)t where t is as defined in relation to formula (I) and Z is a leaving group,
either (a) when R40 is C(O), with a compound of formula (VIII)
HNR15R16xe2x80x83xe2x80x83(VIII)
where R15 and R16 are as defined in relation to formula (I);
or (b) where R40 is group (CH2)t with a compound of formula (IX)
HR17xe2x80x83xe2x80x83(IX)
where R17 is as defined in relation to formula (I);
and thereafter if necessary or desirable, deprotecting a group R2xe2x80x2 to a group R2 or changing a group R2 to a different such group.
Suitable leaving groups for Z include halo such as chloro. The reaction is suitably effected in an organic solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as triethylamine. Moderate temperatures, for example of from 0xc2x0 to 50xc2x0 C. and conveniently ambient temperature may be employed.
The compounds of formula (VII) suitably have an ester group as R2xe2x80x2. Such compounds can then be converted to the corresponding acid by desterification, for example using sodium hydroxide in a mixture of methanol and tetrahydrofuran.
Compounds of formula (VII) where R40 is C(O) are suitably prepared in situ by reaction of the corresponding carboxylic acid with a halogenating agent such as oxalyl chloride. The acid is suitably derived from a compound of formula (X) 
where X, R1, R2xe2x80x2, R3, R5, R6 and R7 are as defined above, by a sequence of reactions in which the hydroxy methyl group is first converted to a carboxaldehyde for example by reaction with 2,3-dichloro-5,6-dicyanobenzoquinone, which is then oxidised to the corresponding acid using conventional methods.
Compounds of formula (X) are suitably prepared by reacting a compound of formula (XI) 
where X, R2xe2x80x2, R3, R5, R6 and R7 are as defined above and R41 is a protecting group, with a compound of formula (XII)
R1xe2x80x94Xxe2x80x94Z1xe2x80x83xe2x80x83(XII)
where R1 and X are as defined in relation to formula (I) and Z1 is a leaving group; and thereafter removing the protecting group R41.
Suitable leaving groups for Z1 include halide such as chloride, bromide or iodide, as well as mesylate or tosylate. The reaction is suitably effected in an organic solvent such as dimethylformamide (DMF) tetrahydrofuran (THF) or DCM in the presence of a base such as sodium hydride, sodium hydroxide, potassium carbonate. Optionally the reaction is effected in the presence of a suitable phase transfer catalyst. The choice of base and solvent is interdependent to a certain extent in that certain solvents are compatible with some bases only as is understood in the art. For example, sodium hydride may preferably be used with dimethylformamide or tetrahydrofuran and sodium hydroxide is preferably used with dichloromethane and a phase transfer catalyst.
The reaction can be carried out at moderate temperatures, for example from 0 to 50xc2x0 C. and conveniently at about ambient temperature.
Preferably, R2xe2x80x2 is an ester group in the compound of formula IX and this may be subsequently converted to an acid or to another ester or salt, by conventional methods later in the process.
Suitable protecting groups R41 include acetyl, benzyl or tetrahydrpyranyl. The reaction conditions employed will be variable depending upon the nature of the protecting group R40 and would be apparent to a skilled person. Acetyl groups may be removed by reaction with a strong base such as sodium methoxide, whereas benzyl groups may be removed by hydrogenation, for example in the presence of a catalyst such as palladium catalyst. Removal of tetrahydropyranyl protecting groups may be effected using p-toluenesulphonic acid as illustrated hereinafter.
Compounds of formula (X) may be prepared by cyclisation of a compound of formula (XIII) 
where R5, R6, R7 and R41 are as defined above and R42 and R43 represent a combination of moieties which can cyclise to form an appropriately substituted pyrrole ring. For example, R42 can be a group of formula xe2x80x94CHxe2x95x90C(R44)N3 where R44 is a group R2 as defined above, or a protected form thereof, and R43 may be hydrogen. Cyclisation to form a compound of formula (XII) may then be effected by heating for example under reflux in an organic solvent, in particular a high boiling aprotic solvent such as xylene or toluene.
Alternatively, R43 may be nitro and R42 may be a group of formula xe2x80x94CH2C(O)R2xe2x80x2 where R2xe2x80x2 is as defined above in relation to formula (VII). These compounds will cyclise in the presence of a catalyst such as palladium on carbon in the presence of hydrogen. The reaction may be effected at moderate temperatures for example of from 0 to 80xc2x0 C., conveniently at about ambient temperature.
Thus examples of compounds of formula (XIII) include compounds of formula (XIV) and (XV) 
Compounds of formula (XIII) where R3 is hydrogen may be prepared for example by reacting a compound of formula (XVI) 
with a compound of formula (XVII)
N3CH2R2xe2x80x2xe2x80x83xe2x80x83(XVII)
where R5, R6, R7, R41, and R2xe2x80x2 are as defined hereinbefore. The reaction may be effected in an organic solvent such as ethanol at low temperatures of from xe2x88x9220 to 0xc2x0 C., suitably at about 0xc2x0 C. The reaction is suitably effected in the presence of a base such as an alkoxide, in particular an ethoxide, for example potassium ethoxide.
Where necessary or desired, R3 can be converted from hydrogen to a different group R3 subsequently in the reaction scheme, using conventional methods.
Compounds of formula (XVII) are suitably prepared by reacting a compound of formula (XVIII)
xe2x80x83R47CH2R2xe2x80x2xe2x80x83xe2x80x83(XVIII)
where R2xe2x80x2 is as defined above and R47 is a leaving group such as halide and in particular bromide, with an azide salt, such as an alkali metal azide salt in particular sodium azide.
Compounds of formula (XV) may be prepared by reacting a compound of formula (XIX) 
where R5, R6, R7, R3, R40 and R2xe2x80x2 are as defined above, with a compound of formula (XX) 
where R2xe2x80x2 is as defined above and R48 leaving group such as hydroxy. Examples of compounds of formula (XX) are oxalates such as diethyloxalate. The reaction is suitably effected in the presence of a base such as sodium hydride in an organic solvent such as THF. Moderate temperatures of from 0xc2x0 to 40xc2x0 C. and conveniently ambient temperature is employed.
Compounds of formula (VII) where R40 is (CH2)t may be prepared by halogenation of a compound of formula (XXI) 
where t, R1, R2xe2x80x2, R3, R5, R6 and R7 are as defined above Compound (X) above is a particular example of a compound of formula (XXI) and others may be prepared by analogous methods to those described for formula (X).
Compounds of formula (XI), (XVI), (XVII), (XVIII), (XIX) and (XX) are either known compounds or they can be prepared from known compounds by conventional methods.
According to a further aspect of the invention there is provided a compound of the formula (I) as defined herein, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use in a method of treatment of the human or animal body by therapy. In particular, the compounds are used in methods of treatment of inflammatory disease.
According to a further aspect of the present invention there is provided a method for antagonising an MCP-1 mediated effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof.
The invention also provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, for use as a medicament.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient faith a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30xcexc or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on Formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain. for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board). Pergamon Press 1990.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the Formula I are useful in treating diseases or medical conditions which are due alone or in part to the effects of farnesylation of rats.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per keg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however preferred.
The invention is further illustrated, but not limited by the following Examples in which the following general procedures were used unless stated otherwise.
Preparation 1
Ethyl N-(3,4-dichlorobenzyl)-4-(2-tetrahydropyranyloxy)methylindole-2-carboxylate
Ethyl-4-(2-tetrahydropyranyloxy)methylindole-2-carboxylate (5.1 g) (Chung-gi Shen et al., Heterocycles, 43, 1996, 891-898) and sodium hydride (741 mg, 60% in mineral oil) were stirred in DMF (100 ml) under argon at ambient temperature for 0 minutes. 3,4-Dichlorobenzyl chloride (2.79 ml) was added and the mixture stirred overnight, then partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was washed with water (2xc3x97150 ml), dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using iso-hexane, then ethyl acetate:iso-hexane (5/95) as eluent to give the product as a yellow oil (4.39 g, 56%); NMR xcex4(CDCl3) 1.40 (t, 3H), 1.50-2.00 (m, 6H), 3.60 (m, 1H), 4.00 (m, 1H), 4.35 (q, 2H), 4.75 (m, 1H), 4.85 (d, 1H), 5.10 (d, 1H), 5.80 (s, 2H), 6.85 (m, 1H), 7.15-7.40 (m, 5H), 7.50 (s, 1H); M/z (+) 462.5 (MH+).
Preparation 2
Ethyl N-(3,4-dichlorobenzyl)-4-hydroxymethylindole-2-carboxylate
Ethyl N-(3,4-dichlorobenzyl)-4-(2-tetrahydropyranyloxy)methylindole-2-carboxylate (4.38 g) and p-toluenesulphonic acid (100 mg) in ethanol (100 ml) was stirred at ambient temperature for 3 hours, then concentrated in vacuo and the residue dissolved in ethyl acetate (100 ml), washed with water (100 ml), dried (MgSO4) and concentrated to give the product as an off-white solid (3.22 g, 90%); NMR xcex4(CD3SOCD3) 1.25 (t, 3H), 4.25 (q, 2H). 4.80 (d, 2H), 5.20 (m, 1H), 5.80 (s, 2H), 6.85 (m, 1H) 7.10 (d, 1H), 7.30 (m, 2H), 7.50 (m, 3H, M/z (+) 378.3 (MH+).
Preparation 3
Ethyl 4-formyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate
Ethyl N-(3,4-dichlorobenzyl)-4-hydroxymethylindole-2-carboxylate (5.17 g) and 2,3-dichloro-5,6-dicyanobenzoquinone (3.10 g) were stirred in dioxane (100 ml) at ambient temperature, overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane (100 ml) and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography using 10% ethyl acetate:iso-hexane as eluent to give product as a yellow solid (4.88 g, 95%); NMR xcex4(CD3SOCD3) 1.30 (t, 3H), 4.30 (q, 2H), 5.90 (s, 2H), 6.85 (m, 1H), 7.90 (m, 1H), 8.00 (m, 1H), 10.22 (s, 1H); M/z (+) 376.3 (MH+).
Preparation 4
N-(3,4-Dichlorobenzyl)-2-ethoxycarbonylindole-4-carboxylic acid
A solution of sodium chlorite (9.70 g) and sodium dihydrogen orthophosphate (13.02 g) in water (50 ml) was added dropwise to a solution of ethyl 4-formyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate (4.47 g) and 2-methylbut-2-ene (50 ml) in tert-butyl alcohol (100 ml) and the mixture stirred for 72 hours at ambient temperature, then concentrated in vacuo and the resulting precipitate was filtered and dried to give the product as an off-white solid (4.16 g. 89%); NMR xcex4(CD3SOCD3) 1.25 (t, 3H), 4.30 (q, 2H)) 5.85 (s, 2H), 6.85 (m, 1H), 7.35 (m, 1H), 7.40 (q, 1H), 7.50 (m, 1H), 7.80 (m, 3H); M/z (xe2x88x92) 390.1 (Mxe2x88x92H+).
Preparation 5
Ethyl 4-chloromethyl-N-(3,4-dichlorobenzyl)indole-2-carboxylate
Ethyl N-(3,4-dichlorobenzyl)-4-hydroxymethylindole-2-carboxylate (0.89 g), dimethylformamide (0.5 ml) and thionyl chloride (189 xcexcl) in dichloromethane (40 ml) were stirred at ambient temperature overnight and the resulting precipitate as filtered and dried in vacuo to give the product as a white solid (0.62 g, 67%); NMR xcex4(CD3SOCD3) 1.30 (t, 3H), 4.30 (q, 2H), 5.10 (s, 2H), 5.85 (s, 2H), 6.90 (m, 1H), 7.30 (m, 3H) 7.55 (m, 3H), M/z (+) 396.2 (MH+).
Preparation 6
Ethyl 5-hydroxyindole-2-carboxylate
Boron tribromide (64.58 g) was added dropwise to a stirred solution of ethyl 5-methoxyindole-2-carboxylate (20 g) in dry dichloromethane (1000 ml) at xe2x88x9278xc2x0 C. under an atmosphere of argon. The reaction was allowed to warm to room temperature and stirred for a further 2 hours. The reaction was poured into ice/saturated aqueous sodium hydrogen carbonate solution with stirring and extracted with ethyl acetate. Combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried (MgSO4). The solution was concentrated in vacuo and the residue was purified by column chromatography using 0-60% diethyl ether iso-hexane as eluent to give product as a white solid (9.02 g, 48%); NMR xcex4(CD3SOCD3) 1.31 (t, 3H), 4.29 (q, 2H), 6.79 (dd, 1H), 6.90 (dd, 1H), 7.22 (d, 1H), 8.84 (s, 1H), 11.52 (brs, 1H), M/z (+) 206 (MH+).
Preparation 7
Ethyl 5-acetoxyindole-2-carboxylate
A stirred solution of ethyl 5-hydroxyindole-2-carboxylate (7.79 g) and DMAP (20 mg) in acetic anhydride (80 ml) was heated at 80xc2x0 C. for 4 hours. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate. Combined organic extracts were washed with hydrochloric acid (2.0 M), saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried (MgSO4). The solution was concentrated in vacuo to give the product as a yellow solid (9.39 g, 100%): NMR xcex4(CD3SOCD3) 1.20 (t, 3H), 2.10 (s, 3H), 4.19 (q, 2H), 6.86 (dd, 1H), 6.97 (d, 1H), 7.20 (s, 1), 7.29 (d, 1H); M/z (+) 248 (MH+).
Preparation 8
Ethyl 5-acetoxy-N-(3,4-dichlorobenzyl)indole-2-carboxylate
3,4-Dichlorobenzyl bromide (5.96 g) was added to a stirred solution of ethyl 5-acetoxyindole-2-carboxylate (5.4 g) and potassium carbonate (6.94 g) in acetonitrile (500 ml) under an atmosphere of argon. The reaction was heated at 80xc2x0 C. for 16 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with water, saturated aqueous sodium chloride and dried (MgSO4). The solvent was removed in vacuo and the residue was triturated with iso-hexane to give the product as a cream solid (5.55 g, 63%): NMR xcex4(CD3SOCD3) 1.27 (t, 3H), 2.27 (s, 3H), 4.28 (q, 2H), 5.82 (s, 2H), 6.90 (d, 1H), 7.09 (dd, 1H), 7.33-7.40 (m, 2H), 7.46 (d, 1H), 7.52 (d, 1H), 7.60 (d, 1H).
Preparation 9
Ethyl N-(3,4-dichlorobenzyl)-5-hydroxyindole-2-carboxylate
Sodium ethoxide (1.86 g) was added to a stirred solution of ethyl 5-acetoxy-N-(3,4-dichlorobenzyl)indole-2-carboxylate (5.55 g) in ethanol (50 ml) under an atmosphere of argon. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue acidified with aqueous hydrochloric acid (2.0 M) and extracted with dichloromethane. Combined organic extracts were washed with water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo and the residue was triturated with hexane/diethyl ether to give the product as a white solid (3.17 g, 92%); NMR xcex4(CD3SOCD3) 1.26 (t, 3H), 4.25 (q, 2H), 5.75 (s, 2H), 6.81-6.91 (m, 2H), 6.98 (d, 1H), 7.19 (s, 1H), 7.29 (d, 1H), 7.38 (d, 1H), 7.50 (d, 1H), 9.06 (s, 1H); M/z (+) 364 (MH+).